The LPS-unresponsive C3H/HeJ mouse strain has been utilized to help elucidate the mechanism of action of bacterial endotoxin (LPS). These mice possess a defect in the LPS-responsiveness of their lymphocytes, macrophages and fibroblasts that is due to a mutation in a single, autosomal co-dominant gene. The biological effects of LPS are probably mediated by an initial interaction of LPS with lymphocytes and/or macrophages since C3H/HeJ mice can be rendered susceptible to LPS-induced lethality, adjuvanticity and tumor necrosis by the adoptive transfer of bone marrow cells from LPS-sensitive mice. These effects may be mediated by a number of biologically active compounds such as prostaglandins, lymphocyte activating factor and tumor-necrosis factor. The LPS gene may play a vital physiological role since it appears to control: 1) susceptibility to Herpes simplex virus and S. typhimurium; 2) immune reactivity of thymocytes and 3) the ability of macrophages to kill tumor cells.